Submissions for variant NM_000136.3(FANCC):c.1603C>T (p.Arg535Cys)

gnomAD frequency: 0.00005  dbSNP: rs185822330

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205662	SCV000260240	uncertain significance	Fanconi anemia	2022-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 535 of the FANCC protein (p.Arg535Cys). This variant is present in population databases (rs185822330, gnomAD 0.02%). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 220016). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000564875	SCV000673336	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The p.R535C variant (also known as c.1603C>T), located in coding exon 14 of the FANCC gene, results from a C to T substitution at nucleotide position 1603. The arginine at codon 535 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001753610	SCV001985781	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in patients with pancreatic ductal adenocarcinoma or breast cancer (Shindo et al., 2017; Dorling et al., 2021; Yin et al., 2022); This variant is associated with the following publications: (PMID: 32659497, Gordon2000[Book], 33471991, 35171259, 28767289)
Sema4, Sema4	RCV000205662	SCV002535100	uncertain significance	Fanconi anemia	2021-08-17	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003407725	SCV004106675	uncertain significance	FANCC-related condition	2022-11-10	criteria provided, single submitter	clinical testing	The FANCC c.1603C>T variant is predicted to result in the amino acid substitution p.Arg535Cys. This variant was reported in an individual with pancreatic ductal adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-97864063-G-A). It is interpreted as a variant of uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/220016/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000205662	SCV002081125	uncertain significance	Fanconi anemia	2018-09-17	no assertion criteria provided	clinical testing